The present invention is directed to compositions containing phospholipids comprised of hydroxyeicosatetraenoic acid derivatives and methods of use in treating dry eye.
Dry eye, also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren""s disease and cicatricial pemphigoid manifest dry eye complications.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp, Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye. Contactologia, volume 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages 849-52 (1998). Examples of phospholipid compositions for the treatment of dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.) and U.S. Pat. No. 5,578,586 (Glonek et al.). U.S. Pat. No. 5,174,988 (Mautone et al.) discloses phospholipid drug delivery systems involving phospholipids, propellants and an active substance.
U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocular inserts in the treatment of dry eye. Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturally occurring tear film.
Another approach involves the provision of lubricating substances in lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses compositions containing glycerin and propylene glycol for treating dry eye.
Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient""s waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive. Transient symptoms of dry eye associated with refractive surgery have been reported to last in some cases from six weeks to six months or more following surgery.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis.
In view of the foregoing, there is a clear need for an effective, convenient treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye.
Mucins are proteins which are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjunctival epithelium of human eyes (Greiner et al., Mucous Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846 (1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucous from a Non-Goblet-Cell Source, British Journal of Ophthalmolog, volume 65, pages 833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been discovered and cloned (Watanabe et al., Human Corneal and Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface, Investigative Ophthalmology and Visual Science, volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new mucin which is secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2, pages 337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebaceous material for lubrication and the corneal refraction of light.
Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells. Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid (xe2x80x9cHETExe2x80x9d) derivatives (Yanni et al, Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, volume 90, pages 307-309 (1989)). Similarly, Marom has reported the production of mucosal glycoproteins in human lung by HETE derivatives (Marom et al., Human Airway Monohydroxy-eicosatetraenoic Acid Generation and Mucous Release, Journal of Clinical Investigation, volume 72, pages 122-127 (1983)).
Agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycocongjugate secretion from conjunctival goblet cells. Experimental Eve Research, volume 63, pages 27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from dessication in vivo, Experimental Eye Research, volume 65, pages 569-574 (1997), liposomes (U.S. Pat. No. 4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), and retinoids (U.S. Pat. No. 5,455,265). However, many of these compounds or treatments suffer from a lack of specificity, efficacy and potency and none of these agents have been marketed so far as therapeutically useful products to treat dry eye and related ocular surface diseases.
U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containing HETE derivatives and methods of use for treating dry eye. Yanni et al. discovered that compositions comprising HETE derivatives increase ocular mucin secretion and are thus useful in treating dry eye. Such compositions, however, only act to increase ocular mucin secretion, leading to the rebuilding of the natural tears. While such compositions are therapeutically useful in treating an underlying cause of dry eye, such compositions may not immediately alleviate the symptoms of dry eye following administration. The inventors of the present invention have invented improved HETE-related molecules and compositions which provide both immediate, as well as long-term, dry eye relief.
HETEs have been shown to incorporate in phospholipids in cell cultures. See, e.g., Substitution of 15-Hydroxyeicosatetraenoic Acid in the Phosphoinositide Signaling Pathway, Journal of Biological Chemistry, volume 266, No. 12, pages 7570-7571 (1991); Human Tracheal Epithelial Cells Selectively Incorporate 15-Hydroxyeicosatetraenoic Acid into Phosphatidylinositol, Am. J. Respir. Cell Mol. Biol., volume 8, pages 273-281 (1993); and Interleukin-4 Enhances 15-Lipoxygenase Activity and Incorporation of 15(S)-HETE into Cellular Phospholipids in Cultured Pulmonary Epithelial Cells, Am. J. Respir. Cell Mol. Biol., volume 20, pages 61-68 (1999). Changjin et al. disclose the synthesis of a phospholipid containing 15-keto-HETE (Synthesis of Phospholipids Bearing a Conjugated Oxo-polyunsaturated Fatty Acid Residue, J. Che. Res. Synop., volume 8, pages 500-501 (1999)). Nowhere in the art, however, have pharmaceutical compositions comprising HETE derivative-containing phospholipids and methods of use for the treatment of dry eye been disclosed or taught.
The present invention is directed to novel phospholipid-HETE derivative compounds, compositions and methods of use. Preferred methods are directed to the treatment of dry eye-type diseases and disorders requiring the wetting of the eye, including symptoms of dry eye associated with refractive surgery such as LASIK surgery. The compositions are preferably administered topically to the eye.
The compositions and methods of the present invention provide the advantages of a two-part system for treating dry eye-type diseases and disorders. The phospholipid-HETE derivatives may act as a pro-drug wherein the HETE derivative is cleaved from the phospholipid in vivo following topical administration to the eye. The released HETE derivative may then act to stimulate mucin production while the free phospholipid may concurrently provide for immediate wetting, tear build-up, lubrication or otherwise improving the dry eye condition of the eye due to its amphipathic and humectant characteristics. Additionally, the use of phospholipid-HETE derivative pro-drugs may enhance the stability of the HETE derivative in its pharmaceutical composition. Since the instability of HETE derivatives may be linked to their free terminal carboxylate in an aqueous environment, xe2x80x9ctying offxe2x80x9d the HETE derivative carboxylate by covalent attachment to the phospholipid backbone may improve the stability of the HETE-containing compositions.
The phospholipid-HETE derivatives of the present invention may also act to stimulate mucin production and concurrently provide for the wetting, tear build-up or lubrication of the eye without the need for cleavage of the HETE from the glycerol backbone.
The present invention is directed to phospholipids comprising HETE derivatives and methods of use in treating dry eye-type diseases and disorders. It is believed that the phospholipid-HETE derivatives stimulate ocular mucin production and/or secretion following topical ocular application, and also provide for the wetting, tear build-up or lubrication of the eye, either as the phospholipid-HETE complex or as the cleaved, individual phospholipid and HETE components following topical application to the eye. The phospholipid-HETE derivatives of the present invention 
are of formula I:
wherein:
R20 is H or CHxe2x95x90CH(CH2)12CH3,
X is O or S;
R1 is H, (Cxe2x95x90O)R4 or CH2R4;
J is O or NH;
R2 is (Cxe2x95x90O)R5;
A is CH2 or O;
R3 is OCH2CH(NH3+)COOxe2x88x92, OCH2CH2NH3+, OCH2CH2N+(CH3)3, OCH2CH(OH)CH2OH, O-inositol, OH, H, or alkyl;
R4 and R5 are independently a HETE derivative; substituted or unsubstituted C12-30 alkyl or alkenyl (the alkenyl group containing one or more double bonds); alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or alkyl-M-Q; wherein the substitution is alkyl, halo, hydroxy, or functionally modified hydroxy; wherein:
M is O or S; and
Q is H, alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) or alkyl(heteroaryl)alkyl; with the proviso that at least one of R4 and R5 must be a HETE derivative;
HETE derivative is a structural fragment of formulas II-XIV: 
wherein:
Y is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
V: 
wherein:
Z and Z1 are H, or ZZ1 is CH2;
B5xe2x80x94D5, E5xe2x80x94G5 and T5xe2x80x94K5 are the same or different and are CH2CH2, CHxe2x95x90CH, or Cxe2x89xa1C;
Y5 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
VI: 
wherein:
X6 is CH2CH2CHxe2x95x90CH, CH2CH2Cxe2x89xa1C, CH2CH2CH2CH2, CH2CHxe2x95x90CHCH2, CH2Cxe2x89xa1CCH2, CHxe2x95x90CHCH2CH2, Cxe2x89xa1CCH2CH2, CH2CHxe2x95x90Cxe2x89xa1CH, or CHxe2x95x90Cxe2x89xa1CHCH2;
K6xe2x80x94T6xe2x80x946L is CH2CH2CH2, CH2CHxe2x95x90CH, CH2Cxe2x89xa1C, CHxe2x95x90CHCH2, Cxe2x89xa1CCH2, or CHxe2x95x90Cxe2x95x90CH;
Y6 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuation, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
VII: 
wherein:
X7is CH2CH2CH2, CH2CHxe2x95x90CH, CH2Cxe2x89xa1C, CHxe2x95x90CHCH2, Cxe2x89xa1CCH2, or CHxe2x95x90Cxe2x95x90CH;
D7xe2x80x94E7 and G7xe2x80x94T7 are the same or different and are CH2CH2, CHxe2x95x90CH, or Cxe2x89xa1C;
Y7 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
VIII: 
wherein:
X8 is C2-C5 alkyl, alkynyl, or alkenyl, or a C3-C5 allenyl group;
J8 is H, free or functionally modified hydroxy group, halo, trihalomethyl, free or functionally modified amino group, free or functionally modified thiol group, C(O)R8, or alkyl;
R8 is H, OH, alkyl, alkoxy, amino, alkylamino, or alkoxyamino;
A8 is direct bond or C1-3 alkyl;
B8 is CH2CH2, cis- or trans-CHxe2x95x90CH, or Cxe2x89xa1C;
Y8 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
IX: 
wherein:
E9xe2x80x94D9 is CH2CH2CH2 or cis-CH2CHxe2x95x90CH; or E9 is trans-CHxe2x95x90CH and D9 is CH(OH) in either configuration, wherein the OH is free or functionally modified; or E9 is CH2CH2 and D9 is a direct bond;
p is 1 or 3 when E9xe2x80x94D9 is CH2CH2CH2 or cis-CH2CHxe2x95x90CH, or when E9 is trans-CHxe2x95x90CH and D9 is CH(OH) in either configuration, wherein the OH is free or functionally modified; or p is 0 when E9 is CH2CH2 and D9 is a direct bond;
G9xe2x80x94T9 is CH2CH2, CH(SR)CH2, or trans-CHxe2x95x90CH;
SR comprises a free or functionally modified thiol group;
n is 0, 2, or 4;
Z9 is CH3, CO2R9, CONR2R3, or CH2OR4;
R9 is H or CO2R9 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester;
NR2R3 forms a free or functionally modified amino group;
OR4 forms a free or functionally modified hydroxy group;
Y9 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
X: 
wherein:
K10 is C2-C7 alkyl, alkenyl, or alkynyl, or a C3-C7 allenyl group;
A10 and X10 are the same or different and are a direct bond, CH2, NR11, O, or S, with the proviso that at least one of A and X is NR11, O, or S;
B10 are both H, or B10B10 together forms a double bonded O, S, or NR11, with the proviso that B10B10 is a double bonded O, S, or NR12 when A10 and X10 are the same or different and are NR11, O, or S;
NR11 and NR12 are the same or different and comprise a free or functionally modified amino group;
D10xe2x80x94E10 and G10xe2x80x94T10 are the same or different and are CH2CH2, CHxe2x95x90CH, or Cxe2x89xa1C;
Y10 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
XI: 
wherein:
A11 , B11 , C11 and D11 are the same or different and are C1-C5 alkyl, alkenyl, or alkynyl, or a C3-C5 allenyl group;
Y11 is Cxe2x95x90O (i.e., a carbonyl), or CH(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
XII: 
wherein:
A12B12, C12 and D12 are the same or different and are C1-C5 alkyl, alkenyl, or alkynyl, or a C3-C5 allenyl group;
Y12 is CH(OH) or CCH3(OH) in either configuration, wherein the hydroxy group can be free or functionally modified, and X12 is CH2, CH(CH3) or C(CH3)2; or
Y12 is CH2, CH(CH3) or C(CH3)2, and is CH(OH) or CCH3(OH) in either configuration, wherein the hydroxy group can be free or functionally modified; and
the wavy line indicates the point of attachment;
XII: 
wherein:
A13, B13, C13 and D13 are the same or different and are C1-C5 alkyl, C2-C5 alkenyl, C1-C5 cyclopropyl, C2-C5 alkynyl, or a C3-C5 allenyl group;
E13 is CH(OH), where the hydroxy group is free or functionally modified;
X13 is (CH2)m or (CH2)mO, wherein m is 1-6, and Y13 is a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, acyl, or a free or functionally modified hydroxy, amino, or thiol group; or
X13xe2x80x94Y13 is (CH2)pY21; wherein p is 0-6; and 
wherein:
W13 is CH2, O, S(O)q, NR18, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)q, CHxe2x95x90N, or CH2NR18; wherein q is 0-2, and R18 is H, alkyl, or acyl;
Z13 is H, alkyl, acyl, halo, trihalomethyl, or a free or functionally modified amino, thiol, or hydroxy group; and
---- is a single or double bond;
or X13xe2x80x94Y13 is cyclohexyl; and
the wavy line indicates the point of attachment;
XIV: 
wherein:
OR14 and OR15 are the same or different and comprise a free or functionally modified hydroxy group;
G14, T14 and Z14 are the same or different and are CH2CH2, cis- or trans-CHxe2x95x90CH or Cxe2x89xa1C;
is Cxe2x89xa1C or cis-CHxe2x95x90CH;
one of A14, B14 is H or CH3, and the other is a free or functionally modified hydroxy group, or A4xe2x80x94B14 comprises a double bonded oxygen as a carbonyl, or A4xe2x80x94B14 is OCH2CH2O;
X is CR16R17(CH2)q or CR16R17(CH2)qO, with q is 0-6;
R16 and R17 are the same or different and are H or CH3;
Y14 is CH3, or a phenyl ring optionally substituted with alkyl, halo, trihalomethyl, acyl, or a free or functionally modified hydroxy, thiol, or amino group;
or X14xe2x80x94Y14 is (CH2)pY2O, p is 0-6, 
wherein:
W14 is CH2, O, S(O)m, NR21, CH2CH2, CHxe2x95x90CH, CH2O, CH2S(O)m, CHxe2x95x90N, or CH2NR21;
m is 0-2;
NR21 is NH or a functionally modified amino group;
J14 is H, alkyl, acyl, halo, trihalomethyl, or a free or functionalized hydroxy, thiol, or amino group; and
---- is a single or double bond;
or X14xe2x80x94Y14 is cyclohexyl; and
the wavy line indicates the point of attachment.
It is believed that all of compounds of formula (I), wherein the HETE ID derivatives are selected from formulas (V)-(XIV) are novel, and that some of the compounds of formula (I), wherein the HETE derivatives are selected from formulas (II)-(IV) are novel.
Included within the scope of the present invention are the individual enantiomers of the formula (I) compounds, as well as their racemic and non-racemic mixtures. The individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials. (Asymmetric Synthesis; J. D. Morrison and J. W. Scott, Eds.; Academic Press Publishers: New York, 1983-1985, volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also be isolated from racemic and non-racemic mixtures by a number of known methods, e.g. by purification of a sample by chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G. Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations by HPLC; A. M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1 (1989)). Those skilled in the art will appreciate that racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution, or even mixing samples having different enantiomeric ratios. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages. Also included within the scope of the present invention are the individual isomers substantially free of their respective enantiomers.
As used herein, wavy line attachments indicate that the configuration may be either alpha (xcex1) or beta (xcex2). Hatched lines indicate the a configuration. A solid triangular line indicates the xcex2 configuration.
As used herein, the terms xe2x80x9cpharmaceutically acceptable saltxe2x80x9d, xe2x80x9cpharmaceutically acceptable esterxe2x80x9d and pharmaceutically acceptable thioesterxe2x80x9d means any salt, ester or thioester, respectively, that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and xe2x80x9cophthalmically acceptable saltxe2x80x9d, xe2x80x9cophthalmically acceptable esterxe2x80x9d and xe2x80x9cophthalmically acceptable thioesterxe2x80x9d means any pharmaceutically acceptable salt, ester or thioester, respectively, that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating.
The term xe2x80x9cfree hydroxy groupxe2x80x9d means an OH. The term xe2x80x9cfunctionally modified hydroxy groupxe2x80x9d means an OH which has been functionalized to form: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; an ester, in which an acyl group is substituted for the hydrogen; a carbamate, in which an aminocarbonyl group is substituted for the hydrogen; or a carbonate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or alkynyloxy-carbonyl group is substituted for the hydrogen. Preferred moieties include OH, OCH2C(O)CH3, OCH2C(O)C2H5, OCH3, OCH2CH3, OC(O)CH3, and OC(O)C2H5.
The term xe2x80x9cfree amino groupxe2x80x9d means an NH2. The term xe2x80x9cfunctionally modified amino groupxe2x80x9d means an NH2 which has been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the appropriate group is substituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriate group is substituted for one or both of the hydrogens; an amide, in which an acyl group is substituted for one of the hydrogens; a carbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl group is substituted for one of the hydrogens; or a urea, in which an aminocarbonyl group is substituted for one of the hydrogens. Combinations of these substitution patterns, for example an NH2 in which one of the hydrogens is replaced by an alkyl group and the other hydrogen is replaced by an alkoxycarbonyl group, also fall under the definition of a functionally modified amino group and are included within the scope of the present invention. Preferred moieties include NH2, NHCH3, NHC2H5, N(CH3)2, NHC(O)CH3, NHOH, and NH(OCH3).
The term xe2x80x9cfree thiol groupxe2x80x9d means an SH. The term xe2x80x9cfunctionally modified thiol groupxe2x80x9d means an SH which has been functionalized to form: a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; or a thioester, in which an acyl group is substituted for the hydrogen. Preferred moieties include SH, SC(O)CH3, SCH3, SC2H5, SCH2C(O)C2H5, and SCH2C(O)CH3.
The term xe2x80x9cacylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to another carbon atom.
The term xe2x80x9calkylxe2x80x9d includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be substituted with other groups, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and i-butyl.
The term xe2x80x9ccycloalkylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9cC1-C5 cyclopropylxe2x80x9d means an alkyl chain of 1 to 5 carbon atoms containing a cyclopropyl group wherein the cyclopropyl group may start, be contained in or terminate the alkyl chain.
The tern xe2x80x9cheterocycloalkylxe2x80x9d refers to cycloalkyl rings that contain at least one heteroatom such as O, S, or N in the ring, and can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred heterocycloalkyl groups include pyrrolidinyl, tetrahydrofturanyl, piperazinyl, and tetrahydropyranyl.
The term xe2x80x9calkenylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkenyl groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term xe2x80x9ccycloalkenylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings containing a carbon-carbon double bond, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
The term xe2x80x9cheterocycloalkenylxe2x80x9d refers to cycloalkenyl rings which contain one or more heteroatoms such as O, N, or S in the ring, and can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred heterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, and dihydrofuranyl.
The term xe2x80x9ccarbonyl groupxe2x80x9d represents a carbon atom double bonded to an oxygen atom, wherein the carbon atom has two free valencies.
The term xe2x80x9caminocarbonylxe2x80x9d represents a free or functionally modified amino group bonded from its nitrogen atom to the carbon atom of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.
The term xe2x80x9clower alkylxe2x80x9d represents alkyl groups containing one to six carbons (C1-C6).
The term xe2x80x9chalogenxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The term xe2x80x9carylxe2x80x9d refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
The terms xe2x80x9caryloxyxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9ccycloalkoxyxe2x80x9d, xe2x80x9cheterocycloalkoxyxe2x80x9d, xe2x80x9calkenyloxyxe2x80x9d, xe2x80x9ccycloalkenyloxyxe2x80x9d, xe2x80x9cheterocycloalkenyloxyxe2x80x9d, and xe2x80x9calkynyloxyxe2x80x9d represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, or alkynyl group, respectively, attached through an oxygen linkage.
The terms xe2x80x9calkoxycarbonylxe2x80x9d, xe2x80x9caryloxycarbonylxe2x80x9d, xe2x80x9cheteroaryloxycarbonylxe2x80x9d, xe2x80x9ccycloalkoxycarbonylxe2x80x9d, xe2x80x9cheterocycloalkoxycarbonylxe2x80x9d, xe2x80x9calkenyloxycarbonylxe2x80x9d, xe2x80x9ccycloalkenyloxycarbonylxe2x80x9d, xe2x80x9cheterocycloalkenyloxycarbonylxe2x80x9d, and xe2x80x9calkynyloxycarbonylxe2x80x9d represent an alkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group, respectively, bonded from its oxygen atom to the carbon of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.
Preferred compounds of the present invention include those of formula I, wherein:
X is 0;
R1 is H or (Cxe2x95x90O)R4;
A is O;
R3 is OCH2CH(NH3+)COOxe2x88x92, OCH2CH2NH3+, OCH2CH2N+(CH3)3, O-inositol,
or OH; and
R5 is a HETE derivative.
Particularly preferred for use in the methods and compositions of the present invention are the following compounds 1-3, whose preparations are detailed in examples 1-3: 